JP2012524126A - Method for treating solid tumors - Google Patents

Abstract

The present invention provides methods relating to novel therapeutic strategies for the treatment of hematological malignancies and inflammatory diseases. Specifically, the method of the present invention has the formula I:
[Chemical 1]

Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound mixed with at least one pharmaceutically acceptable excipient.
[Selection figure] None

Description

  This application enjoys the benefit of US Provisional Patent Application No. 61 / 171,047, filed April 20, 2009. The contents of these application documents are incorporated as part of this specification.

  The present invention relates to the fields of therapeutics and medicinal chemistry. Specifically, the present invention relates to a method of treating certain solid tumors comprising the administration of certain quinazolinone derivatives.

  Cell signaling through 3'-phosphorylated phosphoinositides has been implicated in various cellular processes such as malignant transformation, growth factor signal, inflammation, and immunity. Phosphatidylinositol 3-kinase (PI3-kinase; PI3K), an enzyme involved in the generation of these phosphorylated signaling products, was originally the 3'-hydroxyl group of the inositol ring, and phosphatidylinositol (PI) and its phosphorylation. It has been identified as an activity related to viral oncoproteins that phosphorylate derivatives and growth factor receptor tyrosine kinases.

  PI3-kinase activation is thought to be involved in a variety of cellular responses including cell growth, cell differentiation, and apoptosis. FIG. 1 shows several cellular pathways in which PI3K (shown as p110 and p85) is involved in solid tumor activation.

  The first purification and molecular cloning of PI3-kinase revealed that it was a heterodimer consisting of p85 and p110 subunits. Four class I PI3Ks, designated PI3Kα, β, δ, and γ, have been identified, each of which is composed of a different p110 catalytic subunit and a regulatory subunit. Specifically, p11Oγ interacts with three catalytic subunits that interact with the same regulatory subunit, namely p110α, p110β, and p11Oδ, and another regulatory subunit, p101. p85. The expression patterns of each of these PI3Ks in human cells and tissues are also different.

A description of the identification of the p110δ isoform of PI3-kinase is given in Chantry et al., J. Biol. Chem. , 272: 19236-41 (1997). It is known that the human p110δ isoform is expressed in a tissue-specific manner. High level expression in lymphocytes and lymphoid tissues suggests that this protein is involved in PI3-kinase-mediated signaling in the immune system. The PI3K p110β isoform may also be involved in PI3K-mediated signaling in certain cancers. FIG. 2 shows the relative amounts of these isoforms of p110 in several cancer cell lines. In some solid tumors, p110α was not observed or only a small amount was observed, and p110δ found in many solid tumors was only at a low level. All solid tumors showed high levels of p110β.

  There is a need to treat PI3K-mediated diseases associated with cancer, inflammatory diseases, and autoimmune diseases. Quinazolinone may show significant activity as an inhibitor of p110δ, and in general, quinazolinone compounds are known to be primarily useful in treating blood cancers that express relatively high levels of p110δ. ing. Other PI3K inhibitors used to treat solid tumors are under development, but they are either non-selective inhibitors for several isoforms of p110 or are primarily inhibitors of p110α. It is considered to be. For example, Exelixis XL-147 inhibits p110α and p110δ and p110γ with a similar IC-50, and has a 10-fold lower activity for p110β, and BEZ235 is It is known as a pan-PI3K inhibitor that also functions as mTOR, and GDC-0941 is also known as a p110α inhibitor. Since p110α is involved, for example, in the regulation of glucose and insulin levels, it can be considered that the selectivity is poor, or that inhibitors with high levels of p110α will have irrelevant activity . The present invention provides specific isomers of quinazolinone compounds that are particularly useful in the treatment of solid tumors. This compound exhibits greater activity with respect to p110δ than other isoforms of PI3K, and the properties of this compound that are relevant to the treatment of solid tumors are relatively high activity and high levels as inhibitors of p110β. It is believed that this is due to a combination with oral bioavailability, and this compound exhibits a relatively low level of functional activity against p110α.

  The present invention provides a novel method for treating certain solid tumors using compounds of formula I. In certain embodiments, the present invention provides a compound of formula I:

A method for treating a tumor of a patient comprising administering to the patient an optically active compound represented by the formula: or a pharmaceutically acceptable salt thereof. This optically active compound is mainly the S-isomer described herein, but may contain some R-enantiomer as a minor component. Preferably, the compound used in the method of the present invention is mainly composed of the S-isomer as described in detail below.

  Although the methods of the present invention include delivering the compound by various routes, preferably the compound is administered orally.

  The patient can be any mammal, but in a preferred embodiment, the patient is a human subject.

  Without being bound by theory, it is believed that the antitumor activity of this compound is due to inhibition of p110β by this compound rather than inhibition of p110δ or p110α. Activity was observed in a variety of cancer cells that rarely express p110δ, and some cancer cell lines did not express significant amounts of p110α, but all cancer cell lines tested included p110β. It was expressed.

In addition, Compound I showed relatively low functional activity with respect to p110α in a cell transformation system designed to measure the functional activity of these kinases, but in this assay both p110β and p110δ It is a potent inhibitor against See Example 1. This chicken embryo fibroblast (CEF) transformation system has been reported to be a useful technique for evaluating the functional activity of the PI3K signaling pathway. Denley, et al., “Oncogenic signaling of class I PI3K isoforms,” Oncogene , vol. 27 (18), 2561-74 (2008). Transformation of CEF cells in this assay is dependent on the activity of functional kinases. Kang, et al., Proc. Nat'l Acad. Sci. USA , vol. 103 (5), 1289-94 (2006). In other functional cell-based assays, Compound I showed maximum activity with respect to p110δ and p110β, but relatively little activity with respect to p110α.

  As shown in FIG. 4, 10 μM Compound I is a downstream mediator that activates PI3K in two cancer cell lines, namely T47D (breast cancer) and OVCAR-3 (ovarian cancer) (see FIG. 1). It inhibits Akt phosphorylation. It is also important that T47D has a mutation that leads to activation of p110α and that the effect of Compound I on this cell line is not significantly impeded, which means that the anti-tumor of this compound It further suggests that the activity is associated with effects on other isoforms rather than p110α. This makes it possible to distinguish between Compound I and other known PI3K inhibitors in the study of treatment of solid tumors, and these known PI3K inhibitors are p110α isoforms or p110α and others. It is thought that it acts mainly on the combinations with isoforms of, and thus on all combinations of PI3K and mTOR.

  Compound I is useful in treating certain types of cancer. In certain embodiments, the cancer is a non-hematopoietic cancer. In certain embodiments, the cancer is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, black A solid tumor selected from the group consisting of tumor, neuroendocrine cancer, central nervous system cancer, brain tumor, osteosarcoma, and soft tissue sarcoma. In certain embodiments, the cancer is lung cancer (non-small cell lung cancer, small cell lung cancer), colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, or breast cancer.

  In certain embodiments, the methods of the present invention comprise administering to a patient suffering from any of these cancers an effective amount of Compound I, or a pharmaceutically acceptable salt of Compound I. In a preferred embodiment, Compound I is administered orally. The compound can be administered alone or can be administered in the form of a pharmaceutical composition comprising Compound I mixed with at least one pharmaceutically acceptable excipient.

  In certain embodiments, the cancer is breast cancer, lung cancer, prostate cancer, kidney cancer, or ovarian cancer. In certain embodiments, the methods of the invention administer at least one therapeutically effective amount of another therapeutic agent selected to treat cancer in addition to a compound of formula I, and / or , Further providing other therapeutic measures.

  Accordingly, the present invention relates to an optically active compound represented by the formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical comprising the optically active compound represented by the formula I, or a pharmaceutically acceptable salt thereof. A method of treating a patient's solid tumor comprising the step of administering the composition to the patient, wherein the amount of the optically active compound of formula I or a salt thereof is effective in treating the solid tumor It is an amount.

  In certain embodiments, the solid tumor is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer. Melanoma, neuroendocrine cancer, central nervous system cancer, brain tumor, osteosarcoma, and soft tissue sarcoma. In certain embodiments, the solid tumor is selected from non-small cell lung cancer, small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer.

  For the method of the present invention, Compound I is optically active. Preferably, the S-enantiomer is present in excess of the R-enantiomer in a ratio of at least about 9: 1. In certain embodiments, the S-enantiomer is present in excess of the R-enantiomer in a ratio of at least about 19: 1.

  In a preferred embodiment, Compound I is administered orally. In general, Compound I is administered in a solid dosage form and is usually mixed with a pharmaceutically acceptable diluent or excipient.

  The method of the present invention can be used to treat various types of tumors. In certain embodiments, the cancer is ovarian cancer, kidney cancer, breast cancer, lung cancer, colon cancer, or prostate cancer.

  The patient is a mammal and is generally a human. In certain embodiments, the patient has no effect on chemotherapy treatment or has relapsed after treatment with chemotherapy. The method of the present invention is also useful for reducing the level of p110β activity in a patient.

  The compound of formula I can be administered at a dose of 20-500 mg / day. In certain embodiments, the compound of Formula I is administered at least twice daily. In certain embodiments, the compound of formula I is administered at a dose of 50-250 mg / day. In certain embodiments, the compound of formula I is administered twice daily at a dose of 50-150 mg.

In certain embodiments, the dose of Compound I is selected such that the blood concentration of Compound I is in the range of 40-10,000 ng / ml for 12 hours after administration. In certain embodiments, defining a dose will result in a blood concentration of Compound I in the treated patient ranging from about 100 ng / ml to 6,000 ng / ml. In certain embodiments, a dose is defined such that Compound I has a C _max (peak plasma concentration) in the range of 1,000 ng / ml to 8,000 ng / ml.

  Compound I can be administered orally, transdermally, or by injection or inhalation. In certain embodiments, Compound I is administered orally.

  In another embodiment, the invention relates to a combination for treating cancer comprising administering Compound I to a patient undergoing treatment with other therapeutic agents or other cancer therapies Provide therapy.

  In certain embodiments, other therapeutic agents used with Compound I are docetaxel, mitoxantrone, prednisone, estramustine, anthracycline, (doxorubicin (adriamycin), epirubicin (Elens), and liposomal doxorubicin (Doxyl). ), Taxanes (docetaxel (taxotere), paclitaxel (taxol), and protein-bound paclitaxel (Abraxane)), cyclophosphamide (cytoxan), capecitabine (Xeloda), and 5-fluorouracil (5 FU), gemcitabine (gemzar) ), Methotrexate, vinorelbine (navelbine), EGFR inhibitors such as erlotinib, trastuzumab, herceptin, avastin, platin (cisplatin, carboplatin), temozolomide, inter It is selected from the group consisting of ferron α and IL-2. In certain embodiments, the other therapeutic agent is selected from the group consisting of an EGFR inhibitor, an mTOR inhibitor, platin, and a taxane.

  In certain embodiments, the therapeutic means used with Compound I include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biotherapy, enzyme inhibitor therapy, whole body irradiation, stem cell infusion, stem cell support Bone marrow removal using in vitro, peripheral blood stem cell transplantation treated in vitro, umbilical cord blood transplantation, immunoenzyme method, immunohistochemical staining method, pharmacological study, low LET cobalt 60 gamma radiation therapy, bleomycin, conventional surgical procedure, radiation Selected from the group consisting of therapy, high-dose chemotherapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

  In one embodiment, the method of the present invention obtains a biological sample from the patient, and blood chemistry, chromosomal translocation analysis, needle biopsy, fluorescence in situ hybridization, clinical biomarker analysis, immunohistochemical staining compound Analyzing the biological sample using an analysis means selected from the group consisting of: flow cytometry, or a combination thereof. This analysis should be adjusted to increase or decrease the dose of Compound I, or should treatment with Compound I be terminated, or other therapeutics or treatments added to the treatment with Compound I Providing decision materials that allow the decision of whether or not to do so.

  In certain embodiments, Compound I is administered twice daily for about 28 days, after which administration is withdrawn for at least 7 days.

  The following detailed description is intended to assist in understanding and utilizing the method of the present invention.

It is a figure which shows a part of PI3K signal transduction pathway involved in activation of a solid tumor. FIG. 2 shows the levels of Akt and pAkt and the relative levels of p110 α, β, δ and γ isoforms in six different cancer cell lines. FIG. 7 shows readout in CEF transforming function analysis for relative activity of various isoforms of p110. FIG. 7 shows the effect of 0.01 μM to 10 μM concentration of Compound I on phosphorylation of Akt, GSKβ, and S6 in two cancer cell lines, and is also known as a p110α inhibitor The effect of GDC-0941 on the same phosphorylation is compared. 1 is a diagram showing a reaction scheme for synthesizing compound I. FIG. To illustrate the remarkable oral bioavailability afforded by Compound I, it shows the plasma concentration of Compound I in mice administered with a single oral dose of the compound, and also other quinazolinones having a similar structure Comparison is made with the plasma concentration of the compound (Compound B). FIG. 5 shows dose-dependent inhibition of tumor cell culture growth for two different tumor lines. Administration of Compound I at 30 mg / kg twice a day for 5 weeks completely inhibited tumor xenograft growth, but in control animals that were not treated, the corresponding tumor xenografts These are figures which show that the volume increased even more than twice in the same period. When Compound I was administered 30 mg / kg twice a day for 3 weeks, tumor xenograft growth was markedly inhibited, but in control animals that were not treated, the corresponding tumor xenografts FIG. 4 is a diagram showing that the same period was rapidly expanded. FIG. 10 shows plasma concentration data of Compound I obtained when a single dose of 30 mg / kg of compound was administered to mice implanted with the xenograft described in FIGS. 8 and 9. FIG. 3 is a graph showing plasma concentration data on the first and last days of a multi-day test using healthy mice administered with Compound I at 60 mg / kg / day, 120 mg / kg / day, or 240 mg / kg / day. . The 60 mg / kg dose has been well tolerated, which means that the therapeutic dose (30 mg / kg twice a day) is well tolerated and effective in mice. It is proved that.

  Unless otherwise noted, all technical terms, notations, and other scientific terms and postoperative terms described herein generally facilitate the understanding of those skilled in the art to which this invention pertains. That is the purpose. For some terms, terms having a generally understood meaning are defined herein for clarity of meaning and / or for reference purposes, such as those described herein. It is not necessary to incorporate a definition and show substantial differences from what is commonly understood in the art. Many of the techniques and procedures described or referenced herein are well understood by those skilled in the art and are routinely utilized using conventional techniques. If necessary, procedures relating to the use of commercially available kits and reagents are generally performed according to the protocol and / or parameters indicated by the manufacturer, unless otherwise specified.

  The descriptions of the general methods described herein are for illustrative purposes only. Other alternatives and other embodiments will be readily apparent to those skilled in the art having reference to this specification.

  A group of items connected by the conjunction “or” should not be interpreted as requiring mutual exclusivity within the group of items, but rather as “and / or” unless otherwise stated. Should. Although the items, elements or components of the invention are described or claimed in the singular, the plural is also intended within the scope of the invention unless otherwise indicated.

  The present invention relates to a novel therapy for the treatment of cancer, in particular solid tumors. The present invention provides compounds of formula I:

Or a pharmaceutically acceptable salt thereof, or an optically active compound represented by formula I, or a pharmaceutically acceptable salt thereof, and containing at least one pharmaceutically acceptable salt. Administering to the patient a pharmaceutical composition optionally mixed with a dosage form.

  Compound I used in the methods described herein is optically active, indicating that this compound is composed primarily of one of the two enantiomers. This compound has a single asymmetric center in the acyclic linking group between the quinazolinone moiety and the purine moiety. The asymmetric center in the preferred enantiomer of the compound of formula (I) is the S-isomer described above. Compound I, used in optically active form, mainly contains the S-enantiomer. This compound can be synthesized in optically active form or can be prepared in racemic form (including equal amounts of R and S isomers) and these isomers can be separated can do. A chimeric synthesis of Compound I that results in a very high optical purity S-enantiomer is described herein. Please refer to FIG. For the purposes of the present invention, it is preferred to substantially exclude the R-isomer of the enantiomer from the compound of formula (I), but the method of the present invention comprises the S-isomer as the major component. It can be carried out using a mixture of R-isomer and S-isomer. Usually, this mixture contains less than about 10% of the R-isomer, indicating that the ratio of S-isomer to R-isomer is at least about 9: 1. And preferably contains less than 5% of the R-isomer, indicating that the ratio of S-isomer to R-isomer is at least about 19: 1. Show. In certain embodiments, compounds containing less than 2% of the R-enantiomer are used, indicating an enantiomeric excess of at least about 96%.

  The method of the present invention utilizes an optically active form of compound I (compound of formula I), in which case compound I contains the R-enantiomer as a minor component, Are optically active and contain primarily the S-enantiomer. To clarify this point, the dose of the compound of formula I, or the dose of compound I, is described herein, and these doses indicate the weight of the compound of formula I. It also includes the individual enantiomers that make up the compound.

  Thus, a 100 mg dose of Compound I described herein refers to, for example, the weight of a mixture of enantiomers rather than the specific weight of S-enantiomer. For example, a 100 mg mixture containing 9: 1 S-enantiomer and R-enantiomer can be said to contain about 90 mg S-enantiomer or 19: 1 S-enantiomer and R-enantiomer. A 100 mg mixture containing can be said to contain about 95 mg of the S-enantiomer.

  The method of the present invention is useful in treating cancer, particularly solid tumors. In certain embodiments, the cancer is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma. A solid tumor selected from neuroendocrine cancer, central nervous system cancer, brain tumor, osteosarcoma, and soft tissue sarcoma. In certain embodiments, the cancer is lung cancer (non-small cell lung cancer, small cell lung cancer), colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, or breast cancer.

  The effect of Compound I is thought to be mainly due to inhibition of p110β activity in vivo, and it itself also inhibits p110δ activity. Compound I has a selectivity in the inhibition of p110β and p110δ that is not observed in the inhibition of p110α, and is selective for these two kinases over the other kinases tested so far. It is. Such selectivity is explained by the activity observed in the cellular assay for functional activity, where Compound I inhibits p110β with an EC-50 of about 150 nM, and p110δ Was inhibited with about 50 nM EC-50, but only a very small activity (EC-50 exceeding 2,000 nM) was observed for p110α. Although the activity of the compounds against p110β is less than that for p110δ, since p110β is the major isoform of p110 found in solid tumors, the δ isoform for solid tumor activity compared to the activity for p110β It can be said that the importance of activity is small. Compound I shows activity against tumors that express little or no p110δ (suggesting that they are independent of it) and that p110α is activated (See the description of T47D above) is also consistent with the above discussion, and this indicates that high levels of alpha isoforms This suggests that the sensitivity to Compound I is not decreased.

  Selectivity for p110α is important in the safety profile of Compound I, and p110α plays an important role in insulin signaling and glucose metabolism. Non-selective PI3K inhibitors that also inhibit p110α activity may affect signal transduction and / or glucose metabolism resulting in side effects and unexpected adverse effects not seen with Compound I . The unexpected effects involving Compound I are believed to lead to a decrease.

  Compound I also exhibits selectivity for such PI3K isoforms over other PI3K kinases, DNA-PK (other serine-threonine kinases), and other lipid kinases such as mTOR. This table shows IC-50 for inhibition of the kinase activity of the other lipid kinases described above.

In addition, Compound I showed relatively low functional activity with respect to p110α in a cell transformation system designed to measure the functional activity of these kinases, but in this assay both p110β and p110δ It is a potent inhibitor against See Example 1. This chicken embryo fibroblast (CEF) transformation system has been reported to be a useful technique for evaluating the functional activity of the PI3K signaling pathway. Denley, et al., “Oncogenic signaling of class I PI3K isoforms,” Oncogene , vol. 27 (18), 2561-74 (2008). Transformation of CEF cells in this assay is dependent on the activity of functional kinases. Kang, et al., Proc. Nat'l Acad. Sci. USA , vol. 103 (5), 1289-94 (2006). The readout in this assay is based on the frequency of transformation of CEF cells exposed to a viral vector having the particular p110 isoform of interest. Please refer to FIG.

  In this system, EC-50 for p110α functional activity does not reach the maximum concentration of Compound I tested (2000 nM), and EC-50 for inhibition of p110β functional activity by Compound I is: The EC-50 for inhibition of the functional activity of p110δ by Compound I was about 15 nM.

  Similarly, other functional analyzes of specific isoform inhibition in cell-based studies reveal that Compound I exhibits higher activity on the δ and β isoforms of p110 than p110α. It became. The p110α assay utilized SW3T3 cells stimulated with PDGF, and p110 kinase activity was measured using Akt phosphorylation. p110β activity was measured by lysophosphatidic acid stimulation of Akt phosphorylation in mouse fetal fibroblasts. The activity of p110δ was measured by stimulating cross-linking of anti-FcεR1 antibody against the migration of CD63 to the basophil surface. Finally, the activity of p110γ was measured by fMLP stimulation on the migration of CD63 to the basophil surface. Here again, Compound I showed little inhibition of the α isoform, but showed the greatest activity against the δ and β isoforms.

As shown in FIG. 4, 10 μM Compound I is a downstream mediator that activates PI3K in two cancer cell lines, namely T47D (breast cancer) and OVCAR-3 (ovarian cancer) (see FIG. 1). It inhibits Akt phosphorylation. It is also important that T47D has a mutation that leads to activation of p110α and that the effect of Compound I on this cell line is not significantly impeded, which means that the anti-tumor of this compound It further suggests that the activity is associated with effects on other isoforms rather than p110α.

  Compared to other quinazolinones having a similar structure, the bioavailability of Compound I upon oral administration is very good. For example, FIG. 6 shows that Compound I exhibits a higher plasma drug concentration than other quinazolinone compounds (Compound B) having a similar structure. It should be noted that high peak plasma concentrations were observed when Compound I was orally administered to mice at half the dose of Compound B. The magnitude of the difference in oral bioavailability between Compound I and Compound B observed in this study is notable.

The methods of treatment of the present invention usually involve applying Compound I to a patient in need of treatment for at least one week or one week, in most cases 2 to 4 weeks, and in some cases 1 to 3 months or more. Dosage daily over a period of. The in vivo half-life of Compound I in mice and rats is several hours. See FIG. Thus, in some cases, repeated administration of Compound I daily is desirable to maintain effective plasma concentrations over a long period of time. Can be administered at a frequency of 2 times / day, or 3 times / day, or in certain embodiments, especially when Compound I is administered orally, at a frequency of 4 times / day or more. Can be administered. Compound I can also be administered intravenously at a frequency that maintains an effective plasma concentration over an extended period of time. Preferably, the administration is performed at a frequency that achieves a plasma concentration of at least about 1 μM, or at least 3 μM, or at least 5 μM. FIG. 6 shows that a single oral dose of 20 mg / kg of Compound I can be administered over a period of several hours at a plasma concentration of about 500 ng / ml (greater than 1 μM). This demonstrates that high plasma concentrations, for example, concentrations that are considered to be effective in functional analysis, can be achieved with tolerated doses of Compound I.

  Compound I has been shown to induce apoptosis of various solid tumor cells. FIG. 7 shows that Compound I increased tumor cell culture growth in a dose-dependent manner by measuring the optical density at 459 nm for breast cancer cell line (T47D) and ovarian cancer cell line (OVCAR-3). It shows that it is inhibiting. This demonstrates that exposure to 5-10 μM concentrations of Compound I potently inhibits cell culture growth.

  FIG. 8 shows dose-dependent inhibition determined by measuring tumor volume for growth of ovarian cancer xenograft tumors when treated with Compound I. In animals treated with 30 mg / kg Compound I administered twice daily, tumor volume decreased steadily during 30 days of treatment, but controls that did not receive treatment over the same period of time. In animals, tumor volume increased more than twice. This demonstrates that Compound I is effective in treating solid tumors in vivo.

  Similarly, FIG. 9 shows the effect of Compound I when treating other solid tumor xenografts (A498, human kidney cancer cell line). As shown in the figure, when an A498 tumor-bearing mouse was administered with 30 mg / kg of Compound I twice a day and treated for 20 days, effective antitumor activity was observed in vivo. It was. During this treatment period, the tumor volume of the treated animals was approximately doubled, while the tumor volume in the untreated animals was more than 5 times. This also indicates that Compound I is effective in treating solid tumors in vivo.

  FIG. 10 shows the plasma concentration of Compound I in mice with each of the tumor xenografts used in FIGS. 8 and 9 after a single oral dose of 30 mg / kg of Compound I. In this range, which was the effective amount used in the studies shown in FIGS. 8 and 9, the plasma concentration of Compound I reaches about 5,000-7,000 ng / ml.

  FIG. 11 shows plasma concentration data on the first and last days of a multi-day study using healthy mice administered with Compound I at 60 mg / kg / day, 120 mg / kg / day, or 240 mg / kg / day. FIG. The 60 mg / kg dose has been well tolerated, which means that the therapeutic dose (30 mg / kg twice a day) is well tolerated and effective in mice. It is proved that.

  Compound I was also tested according to a series of tumor cell assays known as NCI panels. As a result, substantial growth inhibition of most of the cancer cell lines shown in the panel has been demonstrated, and Compound I is more common against these cancer cell lines than Compound B used for comparison. Showed great activity. The table below shows the GI-50 values (concentration resulting in 50% growth inhibition, μM) for each compound found in these cell culture assays.

As a means to compare the total activity of these two compounds with respect to various types of solid tumor cells, each compound is considered to be a cell line that exhibits a GI50 value of less than 2 μM, ie, good reactivity. The number of cell lines was determined. Using this measuring means, 1.8% of the cell lines showed good reactivity to Compound B at this concentration, whereas 39% of the cell lines had the same concentration at Compound I. Showed good reactivity. Despite being structurally similar to Compound B, it is clear that Compound I exhibits much greater activity than Compound B on solid tumors.

  The table below shows the number of cell lines for each type of tumor that showed a GI50 value of less than 2 μM for Compound I.

In certain embodiments, the cancer is a solid tumor such as lung cancer (non-small cell lung cancer, small cell lung cancer), colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, or breast cancer. is there. As shown in the table above, breast cancer, kidney cancer, prostate cancer, and central nervous system cancer are highly responsive to Compound I, so in certain embodiments any of these cancers. The method of the present invention is used to treat affected patients.

  In certain embodiments, the cancer is not a hematological cancer and is not, for example, a lymphoma, leukemia, or multiple myeloma. Examples of solid tumors that can be treated by the methods described herein include breast cancer, lung cancer, colon cancer, ovarian cancer, kidney cancer, and prostate cancer.

  In certain embodiments, a compound of formula I may be administered in a therapeutically effective amount for a patient diagnosed as having at least one cancer disclosed as a cancer treatable by the methods of the present invention. Administered.

  A person skilled in the art can determine the therapeutically effective amount based on the health condition, age, weight, and pathological condition of the patient. In certain embodiments, the dose is normalized to the patient's weight. For example, the dose can be expressed as a number (mg / kg) of Compound I (mg) / patient body weight (kg). Doses between about 0.1-100 mg / kg are often considered appropriate, and in certain embodiments, doses of 0.5-60 mg / kg are used. Normalization based on patient weight is particularly useful when patient size is quite different, such as when an effective dose found in a dog is converted to an appropriate dose for a human subject.

  In certain embodiments, the daily dose can be expressed as the total amount / dose of Compound I administered, or the total amount of Compound I administered / day. The daily dose of Compound I is generally between about 10 mg and 1,000 mg. When administered orally, the total daily dose for a human subject is generally between about 50 mg and 750 mg.

  In certain embodiments, the compound of formula I is administered at a dose of 20-500 mg / day.

  In certain embodiments, the compound of formula I is administered at a dose of 50-250 mg / day.

  In certain embodiments, the compound of Formula I is administered at a dose of 25-150 mg / dose and is administered 2-4 times / day (eg, 2 doses of 25-150 mg). Or a 25-150 mg dose 3 times / day, or a 25-150 mg dose 4 times / day). In a preferred embodiment, the patient is treated twice daily with Compound I at a dose of 50 mg to 100 mg, or three times daily with a dose of 50 mg to 100 mg, or four times daily with a dose of 50 mg to 100 mg. Done.

  Treatment with a compound of the present invention is often followed for days, for example, generally, treatment is about 7 days, about 14 days, or about 1 treatment cycle. Continue for 28 days. The treatment cycle is a well-known matter in the field of cancer chemotherapy, and it is often desirable to alternate between a dormancy period of 1-28 days, typically 7 days, or 14 days between treatment cycles. is there.

  In certain embodiments, the methods of the invention provide that the compound of formula I is administered to the patient daily at an initial dose of 20-500 mg and until a clinical effect is obtained, Including increasing the dose. To increase the dose, an increase of about 25, 50 or 100 mg can be used. This dose increase can be performed daily, every other day, twice a week, or once a week.

  In certain embodiments, the methods of the invention administer a compound of Formula I at a dose that provides a clinical effect that lasts for a week or more, or increase the dosage to a level at which the clinical effect can be maintained. Continuing treatment of the patient by reducing the dose. Clinical effects can be monitored by conventional methods such as assessing tumor size and spread (metastasis).

  In certain embodiments, the method of the invention administers a compound of formula I to the patient at an initial dose of 20-500 mg and delivers the dose described above for at least 6 days to 50-500 mg. Including increasing to a total dose of 400 mg / day. This dose can optionally be further increased to about 750 mg / day.

  In certain embodiments, the compound of Formula I is administered at least twice daily. In certain embodiments, the compound is administered three times daily. In certain embodiments, the compound is administered four times per day, or four or more times per day.

  In certain embodiments, the methods of the invention comprise reducing the level of PI3Kβ activity in a patient.

  In certain embodiments, the patient is a human subject. Typically, a patient is a human who has been diagnosed as having the cancer disclosed herein as being treatable with Compound I.

In certain embodiments, the compound is administered at a frequency selected such that the compound's blood concentration is in the range of about 40 ng / ml to 3,000 ng / ml, and 4 Maintain the concentration for ~ 12 hours. In certain other specific embodiments, the dosage and frequency of administration is such that the blood concentration of the compound falls within the range of 75 to 2,000 ng / ml and the concentration is 4 to 12 hours after initiation of administration. Is selected to be maintained. In certain embodiments, the dosage and frequency of administration are selected such that the blood concentration of the compound after administration falls within the range of 100 to 1,000 ng / ml. In certain embodiments, the dosage and frequency of administration are selected such that the blood concentration of the compound falls within the range of 100-500 ng / ml for 12 hours after initiation of administration. Desirably, the dosage and frequency of administration are selected to achieve a plasma concentration of Compound I, ie, a plasma concentration C _max of at least about 500 ng / ml and no more than about 10,000 ng / ml. .

  In certain embodiments, Compound I is administered by oral administration, intravenous administration, transdermal administration, or inhalation. Preferably the compound is administered orally. In certain embodiments, the compound is administered orally at a dose of about 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, or 100 mg, 125 mg, 150 mg, or 200 mg / dose, and at this dose It can be administered once a day, twice a day, three times a day, or four times a day.

  In certain embodiments, the method of the invention comprises at least one selected to treat the cancer or autoimmune disease in the patient in addition to administering to the patient a compound of formula I. Administering one therapeutically effective amount of another therapeutic agent and / or applying a therapeutic measure.

  In certain embodiments, the therapeutic agent is docetaxel, mitoxantrone, prednisone, estramustine, anthracycline, (doxorubicin (adriamycin), epirubicin (Elens), and liposomal doxorubicin (doxyl)), taxane (docetaxel). (Taxotere), paclitaxel (taxol), and protein-bound paclitaxel (Abraxane)), cyclophosphamide (cytoxan), capecitabine (Xeloda) and 5-fluorouracil (5 FU), gemcitabine (Gemzar), methotrexate, vinorelbine (navelbine) ), EGFR inhibitors such as erlotinib, trastuzumab (Herceptin, this drug is only used for women with breast cancer with the HER-2 gene), Avastin, platin (cisplata) Down, carboplatin), temozolomide, interferon alpha, and is selected from the group consisting of IL-2.

  In certain embodiments, the therapeutic agent is selected from the group consisting of an EGFR inhibitor, an mTOR inhibitor, and a taxane.

  In certain embodiments, the therapeutic means is peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biotherapy, enzyme inhibitor therapy, whole body irradiation, stem cell infusion, bone marrow removal using stem cell support Peripheral blood stem cell transplantation, cord blood transplantation in vitro, immunoenzyme method, immunohistochemical staining method, pharmacological research, low LET cobalt 60 gamma radiation therapy, bleomycin, conventional surgery, radiation therapy, high-dose chemotherapy And a group consisting of non-myeloablative allogeneic hematopoietic stem cell transplantation.

  In certain embodiments, the methods of the present invention obtain a biological sample from the patient and perform blood chemistry, chromosomal translocation analysis, needle biopsy, fluorescence in situ hybridization, clinical biomarker analysis, immunohistochemistry Further comprising analyzing the biological sample using an analytical means selected from the group consisting of staining compounds, flow cytometry, or combinations thereof. This analysis provides information on tumor progression and progress of treatment, and the results of this analysis include dose determination, dose adjustment in the treatment cycle, and the continuation or discontinuation of treatment according to the present invention. Useful for making decisions.

  In certain embodiments, the optically active compounds used in the methods of the invention described herein contain an excess of the S-enantiomer shown below, and preferably at least 90% of the S-enantiomer is S- Enantiomers, and less than about 10% of them are enantiomer R isomers.

In certain embodiments, at least 80% of the compounds of Formula I used in the methods described herein are S-enantiomers and less than 20% contain the R-enantiomer isomer. It is out. In certain embodiments, the compound comprises the S-isomer in at least 90%, or at least 95% enantiomeric excess (ee).

  In certain embodiments, the compound is primarily composed of the S-enantiomer, the isomer being at least 66-95%, or about 85-95%, the S-isomer, It is present in excess relative to the R-enantiomer contained therein. In certain embodiments, the compound comprises at least 95% S-enantiomer. More than 99% of the sample of Compound I used in the cell experiments and clinical tests shown in the Examples of the present application was the S-enantiomer, that is, the R-enantiomer was less than 1%.

  As used herein, terms such as “selective PI3Kδ inhibitor” and “selective PI3Kβ inhibitor” refer to each of the PI3Kδ isozymes or PI3Kβ isozymes that are more effective than at least one other isozyme of the PI3K family. Refers to a compound that inhibits. This selective inhibitor also inhibits other isozymes of PI3K, but in order to obtain the same level of inhibitory effect exhibited by other isozymes, a higher concentration is required. The term “selectivity” can also be used for compounds that exhibit an inhibitory effect on a particular PI3-kinase over comparable compounds. A “selective PI3Kδ inhibitor” compound is a compound that has been more commonly referred to as a PI3K inhibitor, such as Waltmannin and LY294002, which are considered non-selective PI3K inhibitors. It is understood that the compound exhibits excellent selectivity for.

  As used herein, the term “treat” refers to the suppression of a disease, ie, stopping the progression of the disease, mitigating the disease, ie, toward remission, or alleviating the disease, ie It refers to reducing the severity of symptoms in at least one of the diseases involved. In certain embodiments, the term “treating” refers to preventing the disease in an animal that has become susceptible to the disease but has not yet been diagnosed with the disease. The term “disease” includes, but is not limited to, medical diseases, illnesses, conditions, syndromes and the like.

  In certain embodiments, the present invention provides methods for treating solid tumors, generally non-hematopoietic cancers. In certain embodiments, the cancer is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma. A solid tumor selected from neuroendocrine cancer, central nervous system cancer, brain tumor, osteosarcoma, and soft tissue sarcoma. In certain embodiments, the cancer is lung cancer (non-small cell lung cancer, small cell lung cancer), colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, or breast cancer. In certain embodiments, the cancer is breast cancer, lung cancer, colon cancer, kidney cancer, ovarian cancer, or prostate cancer.

  In certain embodiments, the present invention provides methods for treating solid tumors involving abnormal or undesirably cell signaling activity mediated by PI3Kβ. In certain embodiments, the solid tumor is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer including metastatic breast cancer, prostate cancer including androgen dependent and androgen independent prostate cancer, eg, metastatic kidney Kidney cancer, including cell carcinoma, hepatocellular carcinoma, such as non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung cancer, including lung adenocarcinoma, such as progressive epithelial or primary Ovarian cancer including peritoneal cancer, cervical cancer, gastric cancer, esophageal cancer, for example, head and neck cancer including squamous cell carcinoma of the head and neck, melanoma, neuroendocrine cancer including metastatic neuroendocrine tumor, for example, Selected from the group consisting of brain tumors including glioma, anaplastic oligodendroglioma, pluripotent glioblastoma, and adult anaplastic astrocytoma, osteosarcoma, and soft tissue sarcoma.

  In certain embodiments, the cancer treated by the methods described herein is a solid tumor with loss of function of PTEN (phosphatase and tensin homolog, phosphatase that functions as a tumor suppressor) activity. Loss of PTEN activity is common in cancer and also increases tumor sensitivity to PI3K inhibitors. The NCI panel includes several cell lines that were found to have mutations in PTEN, 70% of those cell lines were inhibited by Compound I, and two of them were in Compound I. The lack of responsiveness proves that there was no loss of function of PTEN activity. The table below summarizes the cell lines that were sensitive to Compound I and the known mutations in those cell lines. Of these mutations, only PTEN was found to be significantly correlated with the effect of Compound I (p <0.036).

Thus, solid tumors with very little PTEN phosphatase activity are particularly suitable for treatment with Compound I. More recently, Welcome Trust Sanger published publications on the occurrence of PTEN mutations in primary tumor tissues, including breast cancer, central nervous system (CNS) cancer, cervical cancer, endometrial cancer, kidney He points out that PTEN mutations are frequently found in cancer, ovarian cancer, prostate cancer, skin cancer, testicular cancer, and urinary tract tumors. Thus, in certain embodiments, the methods of the present invention include one or more of these specific cancers, or breast cancer, central nervous system (CNS) cancer, cervical cancer, endometrial cancer, kidney cancer, ovarian cancer, It is used to treat patients suffering from PTEN deficient cancer selected from the group consisting of prostate cancer, skin cancer, testicular cancer, and urinary tract tumor.

  In certain embodiments, as shown in FIG. 4, Compound I inhibits Akt phosphorylation, so the methods described herein are useful in target cells that mediate Akt phosphorylation. .

  In the treatment of solid tumors, solid tumors utilize this p110β isozyme rather than p110δ or more than p110δ, so that the compound of formula I does not exhibit good activity against p110β. Convenient. Thus, in certain embodiments, a solid tumor is a tumor that expresses p110β at a level higher than the expression level of p110δ. In certain embodiments, a solid tumor is a tumor that exhibits low levels of p110δ activity, such as a tumor that expresses p110δ less than about 20% of p110β.

  In certain embodiments, the subject of treatment described herein is diagnosed as having at least one cancer described herein as being treatable using a compound of Formula I. Patient. In certain embodiments, the patient has been diagnosed with the cancer described herein and has been shown to be ineffective with treatment with at least one conventional chemotherapy. Yes. Thus, in certain embodiments, the methods of the present invention are for patients in need of more effective treatment despite having received one or more of the aforementioned treatments.

  In certain embodiments, the methods described herein comprise administering to a patient a compound of formula I described herein in combination with a therapy used to treat cancer. . “Treatment” as used herein to treat cancer is a well-known or experimental treatment used to treat cancer, wherein the compound of Formula I is not being used. In certain embodiments, the combination of a compound of formula I and a conventional or experimental treatment used to treat cancer is superior to a treatment that does not utilize these combinations; Provide beneficial and / or favorable therapeutic results. In certain embodiments, the methods of treatment used to treat cancer are well known to those skilled in the art and have been reported in the literature. Treatment methods include, but are not limited to, chemotherapy, a combination of chemotherapy and biotherapy, immunotherapy, radioimmunotherapy, and the use of monoclonal antibodies and vaccines. In certain embodiments, this combination method provides compounds of formula I that are administered simultaneously or within a dosing period for treatment. In certain embodiments, this combination method provides a compound of formula I that is administered before or after therapeutic administration. Details regarding administration in this combination can be determined empirically. The order and timing of administration of the compounds of Formula I according to the chosen treatment regimen will be modified based on the individual patient, the substantial condition of the patient being treated, and generally the judgment of the corresponding physician. Will add.

  Other therapeutic agents used in combination with Compound I include those routinely used in the treatment of solid tumors, specifically docetaxel, mitoxantrone, prednisone, estramustine, anthracyclines, (Doxorubicin (adriamycin), epirubicin (Elens), and liposomal doxorubicin (doxyl)), taxane (docetaxel (taxotere), paclitaxel (taxol), and protein-bound paclitaxel (Abraxane)), cyclophosphamide (cytoxan), EGFR inhibitors such as capecitabine (Xeloda), 5-fluorouracil (5 FU), gemcitabine (Gemzar), methotrexate, vinorelbine (navelbine), erlotinib, trastuzumab (Herceptin, this drug Use only for women was suffering from breast cancer with a child), Avastin, platin (cisplatin, carboplatin), temozolomide, interferon alpha, and the like IL-2.

  In certain embodiments, the methods of the present invention provide, in addition to an effective amount of Compound I, at least one therapeutic agent and / or therapeutic means selected to treat the cancer in the patient. Administration. In certain embodiments, the method of the present invention provides the patient with a compound of formula I in addition to docetaxel, mitoxantrone, prednisone, estramustine, anthracycline, (doxorubicin (adriamycin), epirubicin (Elens), And liposomal doxorubicin (doxyl)), taxane (docetaxel (taxotere), paclitaxel (taxol), and protein-bound paclitaxel (Abraxane)), cyclophosphamide (cytoxan), capecitabine (xeloda), and 5-fluorouracil ( 5 FU), gemcitabine (Gemzar), methotrexate, vinorelbine (navelbine), EGFR inhibitors such as erlotinib, trastuzumab (Herceptin, this drug is only used for women with breast cancer with the HER-2 gene To), including Avastin, platin (cisplatin, carboplatin), temozolomide, interferon alpha, and administering other therapeutic agents therapeutically effective amount selected from IL-2, that.

The compounds of the present invention can be formulated for administration to animals using formulation techniques well known in the art. Suitable routes of administration and formulations suitable for compounds of formula I are described in Remington's Pharmaceutical Sciences , latest edition, Mac Publishing, Easton, PA.

  The compound of the present invention can be administered as it is, but it is usually preferable to administer the compound in the form of a pharmaceutical composition or formulation. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of formula I and a biocompatible pharmaceutical carrier, adjuvant or excipient. This composition may be an oligonucleotide or polynucleotide, oligopeptide or polypeptide, drug or hormone, etc. mixed with a drug containing only the active ingredient, or excipients or other pharmaceutically acceptable carriers In combination with other drugs. Carriers and other ingredients can be considered pharmaceutically acceptable so long as they are compatible with the other ingredients contained in the formulation and are not harmful to the patient.

  The pharmaceutical composition is formulated to contain a suitable pharmaceutically acceptable carrier, and any excipients or auxiliaries that facilitate the incorporation of the active compound into the pharmaceutically acceptable formulation are optional. Can be included. In general, the procedure for administration will depend on the nature of the carrier. For example, formulations for parenteral administration include aqueous solutions of water-soluble active compounds. Suitable carriers for parenteral administration can be selected from saline, buffered saline, dextrose, water, and other physiologically compatible solutions. Preferred carriers for parenteral administration include Hank's solution, Ringer's solution, or physiologically compatible solutions such as physiological buffered saline. For administration to tissues or cells, penetrants suitable for the specific barrier to be permeated will be used in the formulation. Such penetrants are generally well known in the art. For formulations containing proteins, the formulations can include stabilizing agents such as polyhydric alcohols (eg, sucrose) and / or surfactants (eg, nonionic surfactants).

  Alternatively, parenteral formulations can include dispersions and suspensions prepared as suitable oily injection suspensions. Suitable lipophilic solvents or excipients include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, and liposomes. Substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran, can be included in the water-soluble injectable suspension. The suspension may also optionally contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Aqueous polymers that achieve pH-sensitive solubilization and / or sustained release of the active agent, for example, methacrylic polymers such as the EUDRAGIT (TM) series commercially available from Rohm America (Piscataway, NJ) Alternatively, it can be used as a matrix structure. Emulsions such as oil-in-water and water-in-oil dispersions optionally stabilized with emulsifiers and dispersants (surface active substances, surfactants) can also be used. The suspension should contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, tragacanth gum, and mixtures thereof. Can do.

  Liposomes containing the active agent can also be used for parenteral administration. In general, liposomes are derived from phospholipids or other lipid substances. The composition in liposome form can contain other ingredients such as stabilizers, preservatives, excipients and the like. Preferred lipids include phospholipids and phosphatidylcholines (lecithins), which may be natural products or synthetic products. Methods for forming liposomes are well known in the art. See, for example, Prescott (Ed.), METHODS IN CELL BIOLOGY, Vol. XIV, p. 33, Academic Press, New York (1976).

  Pharmaceutical compositions containing a dosage of a drug suitable for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art. Preparations formulated for oral administration may be in the form of tablets, pills, capsules, cachets, dragees, troches, solutions, gels, syrups, slurries, elixirs, suspensions, or powders. For example, a pharmaceutical preparation for oral administration can be prepared by mixing the active compound with solid excipients, optionally crushing the resulting mixture, and adding appropriate auxiliaries as necessary. It can be prepared by processing the obtained mixture of granules to obtain a core material for tablets and sugar-coated tablets. As a preparation for oral administration, a liquid carrier similar to that used for parenteral administration, such as a buffered aqueous solution or a suspension, can be used.

Preferred preparations for oral administration include tablets, dragees, and gelatin capsules. These preparations can contain one or more excipients, such as
a) Diluents such as lactose, dextrose, sucrose, mannitol or sugars containing sorbitol,
b) Binders such as magnesium aluminum silicate and starch derived from corn, wheat, rice, potato, etc.
c) Cellulose substances such as methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, gums such as gum arabic and tragacanth, and proteins such as gelatin and collagen,
d) disintegrating or solubilizing agents such as cross-linked polyvinyl pyrrolidone, starch, agar, alginic acid salts such as alginic acid or sodium alginate, or foaming components;
e) Lubricants such as silica, talc, stearic acid or magnesium salt or calcium salt thereof, and polyethylene glycol,
f) flavorings and sweeteners,
g) colorants or pigments, for example to identify products or to determine the amount (dose) of active compound; and
h) Preservatives, stabilizers, swelling agents, emulsifiers, dissolution promoters, salts for adjusting osmotic pressure, and other components such as buffering agents, but are not limited thereto.

  In some preferred formulations for oral administration, the pharmaceutical composition comprises at least one of the substances shown in group (a), or at least one substance shown in group (b), or group (c) ), At least one substance shown in the group (d), or at least one substance shown in the group (e). Preferably, the composition of the present invention comprises at least one substance shown in each of two groups selected from the above groups (a) to (e).

  Examples of gelatin capsules include push-type capsules formed from gelatin, and sealed soft capsules formed from gelatin and a coating material such as glycerol and sorbitol. Indented capsules can contain the active ingredients mixed with fillers, binders, lubricants, and / or stabilizers and the like. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.

  Dragee cores can be prepared with suitable coatings, such as concentrated sugar solutions, and also include gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution , And organic solvents, solvent mixtures, and the like.

  The pharmaceutical composition can be provided as a salt of the active agent. Salts are more soluble in aqueous and other protic solvents than the corresponding free acids and free bases. Pharmaceutically acceptable salts are well known in the art. Compounds that contain an acidic moiety can form pharmaceutically acceptable salts with suitable cations. Suitable pharmaceutically acceptable cations include, for example, alkali metal (eg, sodium or potassium) or alkaline earth (eg, calcium or magnesium) cations.

Compounds of structural formula (I) that contain a basic moiety can form pharmaceutically acceptable acid addition salts using appropriate acids. For example, Berge, et al. Describe pharmaceutically acceptable salts in detail in J. Pharm. Sci. , 66: 1 (1977). These salts can be prepared in situ during the final isolation or separation of the compounds of the present invention, or individually by reacting the action of the free base with the appropriate acid. You can also.

  Typical acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphor salt, sodium camphorsulfonate , Digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate) , Lactate, maleate, methanesulfonate or sulfate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, Pivalate, propionate, succinate, tartrate, thiocyanate, phosphate or hydrogen phosphate, glutamate, bicarbonate, p-toluenesulfone Salts, and, although there is such undecanoate, and the like. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and oxalic acid, maleic acid, succinic acid And organic acids such as, but not limited to, citric acid.

  Basic nitrogen-containing groups include methyl, ethyl, propyl, and lower alkyl halides such as butyl chloride, bromide, and iodide, dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate. Decyl, lauryl, myristyl, and long-chain alkyl halides such as stearyl chloride, bromide, and iodide, arylalkyl halides such as benzyl bromide and phenethyl bromide, and other drugs And can be quaternized. By doing so, a product having a modified solubility or dispersibility is obtained.

  A composition comprising a compound of the invention formulated with a pharmaceutically acceptable carrier is prepared, contained in a suitable container, and the container is labeled for treatment of the indicated condition . Accordingly, an article of manufacture such as a container is also contemplated that includes an indication regarding the dosage form of the compound of the present invention and instructions for its use. In the present invention, a kit is also intended. For example, the kit can include a pharmaceutical composition in dosage form and a package insert that includes instructions for using the pharmaceutical composition in treating a medical condition. In any case, the pathological condition described in the document can include inflammatory diseases, cancer, and the like.

Method of Administration A pharmaceutical composition comprising a compound of formula I can be administered to a patient by conventional methods including parenteral administration techniques and enteral administration techniques. Parenteral administration methods include routes other than the digestive tract, such as intravenous, intraarterial, intraperitoneal, intramedullary, intramuscular, intraarticular, intrathecal, and intraventricular injection. is there. Examples of enteral administration include oral administration (including buccal and sublingual administration) and rectal administration. Examples of transepithelial administration methods include transmucosal administration and transdermal administration. Examples of transmucosal administration methods include enteral administration and nasal administration, inhalation, and deep lung administration, and vaginal administration and rectal administration. Transdermal administration includes, for example, patches and iontophoresis devices and passive or active transdermal or transmembrane administration methods such as pastes, pastes or ointments. Parenteral administration can also be performed using high pressure techniques such as POWDERJECT ™.

  Surgical techniques include implants such as depot (reservoir) compositions and osmotic pumps. As a preferable administration route for treating inflammation, localized diseases such as arthritis can be administered locally or locally, and distributed diseases such as reperfusion injury and sepsis can be used. As for systemic pathological conditions, systemic delivery can be performed by intravenous administration or the like. For diseases involving the respiratory tract, such as chronic obstructive pulmonary disease, asthma, and emphysema, etc., administration is carried out by inhalation of spray, aerosol, powder, etc. or deep lung administration can do.

  The compounds of formula I can be administered before, during, or after chemotherapy, radiation therapy, and / or surgery. The formulation and route of administration selected will be modified based on the individual patient, the substantial pathology of the patient being treated, and generally the judgment of the corresponding physician.

By altering or inducing a compound that is targeted for delivery to a cancer cell expressing a marker that identifies the cancer cell, the therapeutic index of the compound of Formula I can be improved. For example, by linking the compounds to an antibody that recognizes a marker that is selective or specific for cancer cells, as described above, the compounds gather near the cancer cells where they are localized. (E.g. Pietersz, et al, Immunol. Rev. , 129: 57 (1992); Trail et al, Science , 261: 212 (1993); and Rowlinson-Busza, et al, Curr. Qpin. Oncol ., 4: 1142 (1992)). Delivery of these compounds directly to the tumor will lead to improved therapeutic utility, especially by minimizing non-specific strong toxicity resulting from radiation therapy or chemotherapy. In other embodiments, a compound of Formula I and a radioisotope or chemotherapy can be used in combination with the same anti-tumor antibody.

  The nature of the drug itself and the formulation using the drug can affect the physical state, stability, release rate in vivo, and clearance rate in vivo of the administered drug. Such information on pharmacokinetics and pharmacodynamics can be gathered in in vitro and in vivo preclinical studies and will later be confirmed for humans in the course of clinical trials. Accordingly, for any compound used in the method of the present invention, a therapeutically effective dose can be estimated initially from a biochemical assay and / or an assay using cells.

Toxicity and therapeutic effects of the compounds of the present invention can be determined by standard pharmaceutical procedures using cell cultures or laboratory animals, such as LD ₅₀ (dose that kills 50% of the population) or ED ₅₀ ( _{50 of the} population). The determination can be made by a technique that determines the dose that shows therapeutic efficacy in%. The dose ratio between toxic and therapeutic effects is the “therapeutic index”, usually expressed as the ratio LD50 / ED50. Compounds with a high therapeutic index are preferred, i.e. compounds with a toxic dose that is substantially greater than the effective dose. Data obtained from the cell culture assays described above and other animal experiments can be used to derive dose ranges for human application. The doses of these compounds are preferably within a range of circulating concentrations that include the ED ₅₀ and with little or no toxicity.

  In the method of the present invention, an effective administration plan in which the administration time and the administration order are determined can be used. The dose of the drug preferably comprises a pharmaceutical dosage unit containing an effective amount of the drug. As used herein, the term “effective amount” refers to modulation of PI3Kβ expression or activity, and / or measurement of a patient's physiological parameters by administering one or more pharmaceutical dosage units. It refers to an amount sufficient to induce possible changes. The term “effective amount” also refers to the amount necessary to alleviate a disease or disorder in a patient.

  Suitable dosage ranges for compounds of formula I will vary in light of these, but in general, these compounds range from 10.0 μg / kg body weight to 15 mg / kg body weight, 1.0 It is administered in the range of μg / kg body weight to 10 mg / kg body weight, or 0.5 mg / kg body weight to 5 mg / kg body weight. Thus, for a standard 70 kg human subject, this dose range would be 700 μg / dose to 1050 mg / dose, 70 μg / dose to 700 mg / dose, or 35 mg / dose to 350 mg / dose, and at these doses Administration is performed twice or more times a day. When these compounds are administered orally or transdermally, their dosage can be increased compared to, for example, intravenous administration. In certain embodiments, the treatment of cancer comprises oral administration of Compound I up to 750 mg / day. Suppressing the toxicity of this compound allows administration for treatment at relatively high doses. To treat many solid tumors, it is appropriate to administer orally at a frequency of about 50-100 mg / dose once a day, or preferably at least twice a day. Often there is. In certain embodiments, Compound I is orally administered at a total daily dose of between about 60-750 mg and 20-150 mg / dose in 3-5 doses per day. In certain embodiments, the total daily dose is between 100 and 500 mg, and in certain embodiments, the normalized daily dose (value adjusted based on patient weight) is Up to about 60 mg / kg body weight

  These compounds can be administered as a single bolus dose or as a dose over time in intravenous administration, transdermal administration, or multiple administration. A dose can be delivered over time for intravenous or transdermal delivery, and a dose can be selected or adjusted to achieve the desired plasma concentration for the active compound. In certain embodiments, the desired concentration will be at least about 1 μM, alternatively at least about 10 μM.

  When the compound is administered orally, it is preferable to administer 2 or 3 doses per day. In certain embodiments, 3 doses / day are being administered. In certain embodiments, 4 doses / day are administered.

  Dosing may be for only one day or may take place over multiple days of about 7 days. In certain embodiments, daily dosing is continued for about 14 days or about 28 days. In certain embodiments, the dosing is continued for about 28 days, then the dosing is stopped for the next 7 days, and the therapeutic effect is assessed during the rest period when treatment with Compound I is discontinued, and Once the treatment has been evaluated to produce the desired effect, Compound I can be used to resume treatment for a further 7-28 day cycle.

  Based on body weight, body surface area, or organ size, an appropriate dose according to the administration route can be calculated. The final dosing regimen includes various factors that modify the action of the drug, such as the specific activity of the drug, the substance and severity of the disease, the patient's responsiveness, the patient's age, condition, weight, sex, and It will be determined by the treating physician from the viewpoint of proper medical practice, taking into account the eating habits and the severity of the infection. Other factors to consider include timing and frequency of administration, drug combinations, response sensitivity, and resistance / response to treatment. Further adjustment of the appropriate dose in treatments involving any of the formulations described herein includes, inter alia, information regarding the doses and assays described herein, as well as clinical trials in humans. Considering the pharmacokinetic data obtained in (1) above, this is an item that can be easily realized by those skilled in the art without undue experimentation. Appropriate doses can be determined using established assays for determining the concentration of drugs in body fluids and other analytes along with dose response data.

  The frequency of taking will vary depending on the pharmacokinetic parameters of the drug and the route of administration. Dosages and administration methods are adjusted to keep the active moiety at a sufficient concentration or to maintain the desired effect. Thus, the pharmaceutical composition may be administered as a single dose, multiple doses, continuous infusion, sustained release depot, or combinations thereof as needed to maintain the desired minimum concentration of drug. Can do. Short-acting pharmaceutical compositions (ie, short half-life) have a frequency of once a day, or once or more a day (eg, twice, three times, or four times a day) Can be administered. The long-acting pharmaceutical composition can be administered every 3-4 days, every week, or once every two weeks. Pumps such as subcutaneous, intraperitoneal, or subdural pumps can be suitably utilized for continuous infusion.

  Patients who will respond favorably to the method of the present invention include medical patients and veterinary patients, and generally include human patients. Among other animals, animals for which the method of the present invention is useful include cats, dogs, large animals, and birds such as chickens. In general, if a patient benefits from a compound of formula I, it is appropriate to receive it according to the method of the present invention.

  The biological data disclosed herein was generated using a sample of Compound I containing less than 1% R-isomer and greater than 99% S-enantiomer at 40 ° C. and 90%. : Determined by chiral HPLC using a 4.6 × 250 mm Chiralcel OD-H column operated with 10 hexane / ethanol at a flow rate of 1 ml / min. This material was prepared according to the procedure summarized in FIG. This material has been determined to be> 99% pure by HPLC (by detection of UV light at 214 nm and 254 nm), and has also been identified by NMR and electrospray mass spectrometry. It was in the form of a white powder.

  The materials used in the examples had the following properties.

Example 1: Chicken Embryo Fibroblast Transformation Assay
Chicken embryo fibroblasts (CEF) are transduced with viral stocks having human gene types in each of the PI3K isoforms p110α, p110β, p110δ, and p110γ. These transduced CEF strains are then seeded in a growth medium that can later be stained and counted for tumorigenically transformed cell morphology. Compound I inhibited the formation of transformed foci in CEF cells transduced with p110β exhibiting an EC50 of 150 nM. In contrast, even the highest concentration (2,000 nM) of Compound I used in the study did not significantly inhibit CEF cells transduced with p110α. Denley A, Kang S, Karst U and Vogt PK, "Oncogenic signaling of class 1 PI3K isofoms," Oncogene (2008) 27: 2561-2574. FIG. 3 illustrates the readout of this assay.

Example 2: Preparation of Compound I
Using methods well known in the art, including variations of the methods described in Zhichkin, et al., Organic Letters , vol. 9 (7), 1415-18 (2007), and US Pat. No. 6,800,620. Compound I was synthesized via the route shown in FIG.

Example 3: Effect of Compound I on Ovarian Cancer Cell Xenografts
Female nu / nu mice bearing OVCAR-3 xenografts (human ovarian cancer cells) were maintained until their tumor volume was approximately 100 mm ³ . At that time, 30 mg / kg of Compound I was administered twice a day to initiate treatment. The measurement results of the tumor volume over 36 days are shown in FIG. 8, which shows that the treatment with Compound I not only inhibited tumor growth but also the actual tumor size. It is a demonstration of shrinking.

Example 4: Effect of Compound I on Renal Cancer Xenografts
Female nu / nu mice bearing A498 xenografts (human kidney cancer cells) were maintained until the tumor volume was approximately 100 mm ³ . At that time, 30 mg / kg of Compound I was administered twice a day to initiate treatment. Tumor volume measurements over 20 days are shown in FIG. 9, which demonstrates that in vivo tumor growth is significantly inhibited with the dose levels used here. Is.

Example 5: Plasma concentration of Compound I in mice with tumor xenografts Plasma of Compound I for female nu / nu mice with either of the cancer cell xenografts used in the previous two examples The medium concentration was examined. Each test animal received a single dose of Compound I at a dose of 30 mg / kg and was monitored for plasma concentrations over the subsequent 12 hours. As shown in FIG. 10, in any case, the plasma concentration of Compound I peaks about 2 to 4 hours after administration, and a single dose is administered at the previous dose. After 8 hours, the value returned to almost zero. The peak plasma concentration in these animals is the dose that is effective in inhibiting tumor growth in each xenograft (see previous examples and FIGS. 8-9). ), Which were observed after a single injection, but generally were below about 7,000 ng / ml.

Example 6: Pharmacokinetics and toxicokinetics of Compound I in rats Compound I is prepared to give a dose of 60, 120, or 240 mg / kg / day and is administered to healthy rats as a single dose As a result, the administration was performed by the 14th day. FIG. 11 shows the blood concentration of Compound I measured over a 24-hour period for each test animal between the first day of treatment (dashed line) and the last day of treatment (solid line) performed for tolerance. ing. The peak concentration of Compound I (C _max ) and the area under the concentration curve (AUC) for tolerability are both greater than those observed with an effective dose of Compound I in mouse xenograft model tumors. It was. For example, in a dose of 60 mg / kg / day, although the C _max of 7,300ng / ml is obtained, C _max on Effective antitumor doses in xenografts in 2,800ng / ml and 5,600ng / ml there were. Similarly, the AUC obtained in this study at a dose of 60 mg / kg / day was 58,000 ng-h / ml compared to having a xenograft and receiving a therapeutically effective dose. Corresponding AUCs in mice were 15,000 ng-h / ml and 18,000 ng-h / ml.

Example 7: Embodiments of the Present Invention The following list lists various embodiments of the present invention.

  1. In certain embodiments, the present disclosure provides a compound of formula I for use as a medicament for treating a solid tumor in a patient:

A pharmaceutical composition comprising the optically active compound of formula I, a pharmaceutically acceptable salt thereof, or the optically active compound of formula I, or a pharmaceutically acceptable salt thereof.

  2. In certain embodiments, the present disclosure provides a compound of formula I for use in treating a solid tumor in a patient:

And a pharmaceutical composition comprising the optically active compound represented by formula I, a pharmaceutically acceptable salt thereof, or the optically active compound represented by formula I, or a pharmaceutically acceptable salt thereof: The amount of the compound of formula I, or a salt thereof, is an amount that is effective in treating solid tumors.

  3. In certain embodiments of embodiment 2, the solid tumor is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck. Selected from the group consisting of cervical cancer, melanoma, neuroendocrine cancer, central nervous system cancer, brain tumor, osteosarcoma, and soft tissue sarcoma.

  4). In certain embodiments of embodiment 2, the solid tumor is selected from non-small cell lung cancer, small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer.

  5). In certain embodiments of embodiment 2, the S-enantiomer is present in excess of the R-enantiomer in a ratio of at least about 9: 1.

  6). In certain embodiments of embodiment 2, the S-enantiomer is present in excess of the R-enantiomer in a ratio of at least about 19: 1.

  7). In any of the embodiments 2-6, the compound is administered orally to the patient.

  8). In any of the embodiments 2-6, the compound is administered to the patient in a solid dosage form.

  9. In an embodiment of embodiment 8, the solid dosage form comprises an optically active compound of formula I mixed with at least one pharmaceutically acceptable excipient.

  Ten. In an embodiment of embodiment 9, the solid tumor is ovarian cancer, kidney cancer, breast cancer, lung cancer, colon cancer or prostate cancer.

  11． In any of the embodiments 2-6, the patient has no effect when receiving chemotherapy treatment or has relapsed after receiving treatment with chemotherapy.

  12． In any of the preceding embodiments, the compound of Formula I is administered at a dose of 20-500 mg / day.

  13. In any of the preceding embodiments, the compound of Formula I is administered at a dose of 50-250 mg / day.

  14. In any of embodiments 2-6, the compound of formula I is administered twice daily at a dose of 50-150 mg.

  15． In any embodiment of embodiments 2-6, the compound of formula I is administered at least twice / day.

  16． In any of embodiments 2-6, the compound further reduces the level of PI3Kδ activity in said patient.

  17． In any of the embodiments 2-6, the patient is a human subject.

  18． In an embodiment of embodiment 17, the blood concentration of the compound is in the range of 40 to 3,000 ng / ml for 12 hours after administration.

  19. In an embodiment of embodiment 17, the blood concentration of the compound in the treated patient is in the range of about 100 nM to 2,000 nM.

  20． In any of the embodiments 2-6, the medicament is administered orally, intravenously or by inhalation.

  twenty one. In any of embodiments 2-6, in addition to the compound of formula I, at least one therapeutically effective amount of a therapeutic agent selected to treat the solid tumor in the patient is administered. And / or provide therapeutic means.

  twenty two. In an embodiment of embodiment 21, the therapeutic agent is docetaxel, mitoxantrone, prednisone, estramustine, anthracycline, (doxorubicin (adriamycin), epirubicin (Elens), and liposomal doxorubicin (Doxyl)), taxane ( Docetaxel (taxotere), paclitaxel (taxol), and protein-bound paclitaxel (Abraxane)), cyclophosphamide (cytoxan), capecitabine (Xeloda), and 5-fluorouracil (5 FU), gemcitabine (Gemzar), methotrexate, EGFR inhibitors such as vinorelbine (navelbine), erlotinib, trastuzumab, herceptin, avastin, platin (cisplatin, carboplatin), temozolomide, interferon alpha, and IL It is selected from the group consisting of -2.

  twenty three. In an embodiment of embodiment 21, the therapeutic agent is selected from the group consisting of an EGFR inhibitor, an mTOR inhibitor, platin, and a taxane.

  twenty four. In an embodiment of embodiment 21, the therapeutic means uses peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biotherapy, enzyme inhibitor therapy, whole body irradiation, stem cell infusion, stem cell support Bone marrow removal, in vitro peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme method, immunohistochemical staining compound, pharmacological study, low LET cobalt 60 gamma radiation therapy, bleomycin, conventional surgery, radiation therapy, high dose Selected from the group consisting of chemotherapy and non-myeloablative allogeneic hematopoietic stem cell transplantation.

  twenty five. In any one of embodiments 2-6, a biological sample is obtained from the patient and blood chemistry, chromosomal translocation analysis, needle biopsy, fluorescence in situ hybridization, clinical biomarker analysis, immunohistochemistry Further comprising analyzing the biological sample using an analytical means selected from the group consisting of staining compounds, flow cytometry, or combinations thereof.

  26. In an embodiment of embodiment 25, the compound is administered twice daily for about 28 days, after which the administration is withdrawn for at least 7 days.

Claims (26)

Formula I used as a medicament for treating solid tumors in patients:
Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the optically active compound represented by formula I or a pharmaceutically acceptable salt thereof. An amount of Formula I used to treat a patient's solid tumor and effective in treating the solid tumor:
Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the optically active compound represented by formula I or a pharmaceutically acceptable salt thereof.   The solid tumor is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine 3. The compound of claim 2, selected from the group consisting of cancer, central nervous system cancer, brain tumor, osteosarcoma, and soft tissue sarcoma.   3. The solid tumor of claim 2, wherein the solid tumor is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer. Compound.   The compound of claim 2, wherein the S-enantiomer is present in excess of the R-enantiomer in a ratio of at least about 9: 1.   The compound of claim 2, wherein the S-enantiomer is present in excess of the R-enantiomer in a ratio of at least about 19: 1.   The compound according to any one of claims 2 to 6, which is orally administered to the patient.   The compound according to any one of claims 2 to 6, which is administered to the patient in a solid dosage form.   9. A compound according to claim 8, wherein the solid dosage form comprises an optically active compound of formula I mixed with at least one pharmaceutically acceptable excipient.   The compound according to claim 9, wherein the solid tumor is ovarian cancer, kidney cancer, breast cancer, lung cancer, colon cancer, or prostate cancer.   7. The compound according to any one of claims 2 to 6, wherein the patient has no effect even after chemotherapy treatment, or has relapsed after treatment with chemotherapy.   7. A compound according to any of claims 2 to 6, wherein the compound of formula I is administered at a dose of 20 to 500 mg / day.   7. A compound according to any of claims 2 to 6, wherein the compound of formula I is administered at a dose of 50 to 250 mg / day.   7. A compound according to any of claims 2 to 6, wherein the compound of formula I is administered twice daily at a dose of 50 to 150 mg.   7. A compound according to any of claims 2 to 6, wherein the compound of formula I is administered at least twice / day.   7. The compound of any one of claims 2 to 6, further comprising reducing the level of PI3Kδ activity in the patient.   The compound according to any one of claims 2 to 6, wherein the patient is a human.   18. A compound according to claim 17 wherein the compound has a blood concentration in the range of 40 to 3000 ng / ml for 12 hours after administration.   18. A compound according to claim 17, wherein the blood concentration of said compound in a treated patient is in the range of about 100 nM to 2000 nM.   The compound according to any one of claims 2 to 6, wherein the drug is administered orally, intravenously or by inhalation to a patient.   In addition to administering to the patient a compound of formula I, administering at least one therapeutically effective amount of a therapeutic agent selected to treat the cancer in the patient and / or therapeutic means The compound according to any one of claims 2 to 6, further comprising:   The therapeutic agent is docetaxel, mitoxantrone, prednisone, estramustine, anthracycline, (doxorubicin (adriamycin), epirubicin (Elens), and liposomal doxorubicin (doxyl)), taxane (docetaxel (taxotere), paclitaxel ( Taxol), and protein-bound paclitaxel (Abraxane)), cyclophosphamide (Cytoxan), capecitabine (Xeloda), and 5-fluorouracil (5-FU), gemcitabine (Gemzar), methotrexate, vinorelbine (Navelbine), erlotinib Selected from the group consisting of EGFR inhibitors such as trastuzumab, herceptin, avastin, platin (cisplatin, carboplatin), temozolomide, interferon α, and IL-2 The compound of claim 21 which is.   23. The compound of claim 21, wherein the therapeutic agent is selected from the group consisting of an EGFR inhibitor, mTOR inhibitor, platin, and taxane.   Peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biotherapy, enzyme inhibitor therapy, whole body irradiation, stem cell injection, bone marrow removal by stem cell support, peripheral blood in vitro Stem cell transplantation, cord blood transplantation, immunoenzymatic method, immunohistochemical staining compound, pharmacological study, low LET cobalt 60 gamma radiation therapy, bleomycin, conventional surgery, radiation therapy, high dose chemotherapy, and non-myeloablative 24. The compound of claim 21, selected from the group consisting of allogeneic hematopoietic stem cell transplantation.   Obtain a biological sample from the patient and from blood chemistry, chromosomal translocation analysis, needle biopsy, fluorescence in situ hybridization, clinical biomarker analysis, immunohistochemical staining compound, flow cytometry, or a combination thereof The compound according to any one of claims 2 to 6, further comprising analyzing the biological sample using an analysis means selected from the group consisting of:   26. The compound of claim 25, wherein the compound is administered to the patient twice daily for about 28 days, followed by withdrawal for at least 7 days.